In-Depth Study of Tripeptide-Based α-Ketoheterocycles as Inhibitors of Thrombin. Effective Utilization of the S<sub>1</sub>‘ Subsite and Its Implications to Structure-Based Drug Design.

Costanzo, Michael J.; Almond, Harold R.; Hecker, Leonard R.; Schott, Mary R.; Yabut, Stephen C.; Zhang, Han‐Cheng; Andrade‐Gordon, Patricia; Corcoran, Thomas W.; Giardino, Edward C.; Kauffman, Jack A.; Lewis, Joan M.; Garavilla, Lawrence de; Haertlein, Barbara J.; Maryanoff, Bruce E.

doi:10.1021/jm701211q

Cited by 15 publications

(30 citation statements)

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“…We examined the method validation on different series of isoselective RCA inhibitors targeted at enzymes with published K i and IC50 values: the serine proteases thrombin,23 trypsin,23 and human neutrophil elastase (HNE);24 the serine hydrolase fatty acid amide hydrolase (FAAH);25 the cysteine proteases cathepsin K,26 3C HRV,27 and caspase 3 28. In the present work, the reaction core of CS is a carbonyl group substituted by a varying X (Inh in Fig.…”

Section: Resultsmentioning

confidence: 99%

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EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

Traube

Vijayakumar

Hirsch

et al. 2010

J. Chem. Inf. Model.

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We introduce an enzyme mechanism-based method, EMBM, aimed at rational design of chemical sites, CS, of reaction coordinate analog inhibitors. The energy of valence reorganization of CS, caused by the formation of the enzyme-inhibitor covalent complex, is accounted for by new covalent descriptors W1 and W2. We considered CS fragments with a carbonyl reactivity center, like in native protease substrates. The W1 and W2 descriptors are calculated quantum mechanically on small molecular clusters simulating the reaction core of the formed covalent tetrahedral complex -anionic TC(O−) or neutral TC(OH). The modeling on a reaction core allows generation of various CS and corresponding TC(O−) and TC(OH) as universal building blocks of real inhibitors and their covalent complexes with serine or cysteine hydrolases. Moreover, the approach avoids the need for 3D structure of the target enzyme, so EMBM may be used for ligand-based design. We have built a Chemical Site of Inhibitors (CSI) databank with pairs of W1 and W2 descriptors pre-calculated for both CH 3 O(−) and CH 3 S(−) nucleophiles for every collected CS fragment. We demonstrated that contribution of a CS fragment to the binding affinity of an inhibitor depends on both its covalent reorganization during the chemical transformation and its non-covalent interactions in the enzyme active site. Consequently, prediction of inhibitors binding trend can be done only by accounting for all of these factors, using W1 and W2 in combination with non-covalent QSAR descriptors.

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Section: Resultsmentioning

confidence: 99%

“…2a) and compounds from Table 1 in Ref. 23b as a test set (Fig. 2b) for the serine proteases thrombin and trypsin.…”

Section: Resultsmentioning

confidence: 99%

EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

Traube

Vijayakumar

Hirsch

et al. 2010

J. Chem. Inf. Model.

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“…A group at Johnson & Johnson resumed earlier developments [170,171] of a thrombin inhibitor that probes the S 1 ′ binding site [172]. The design of these inhibitors is based on the idea of substituting the X in the known thrombin recognition motif D-Phe-Pro-Arg-X (see also PPACK,9) with heterocycles that would (i) increase the electrophilicity of the arginine carbonyl such that it would form a hemiketal adduct with the γ-oxygen of the activesite Ser195 and (ii) extend interactions with thrombin into the S 1 ′ binding site.…”

Section: New Inhibitors -Old Principlesmentioning

confidence: 99%

“…Inhibitor 37 also proved to be a potent trypsin inhibitor but was slightly less selective over coagulation enzymes compared with 36. However, inhibitor 37 exibited significantly diminished cardiovascular side effects and had an improved profile with respect to therapeutic index [172]. The inhibitory activity of 2-substituted benzoxazinones toward serine proteases has been known for more than two decades [174][175][176], and structural information on inhibitor-protease complexes is available [177].…”

Section: New Inhibitors -Old Principlesmentioning

confidence: 99%

Direct thrombin inhibitors – a survey of recent developments

Schwienhorst¹

2006

Cell. Mol. Life Sci.

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Thrombin is a plasma serine protease that plays a key role in coagulation and hemostasis but also in thromboembolic diseases. Direct thrombin inhibitors could, therefore, be beneficial for future anticoagulant therapy in the prophylaxis of venous and arterial thrombosis as well as myocardial infarction. However, development of direct thrombin inhibitors has brought researchers more heartache than success. The most recent setback came this year when AstraZeneca withdrew Ximelagatran, the first orally bioavailable direct thrombin inhibitor that had received regulatory approval (France, 2003), after reports of serious hepatoxicity in a fraction of patients. This review describes the status of direct thrombin inhibitors, focusing on drug candidates that are at present in clinical trials. In addition, some more recent research strategies in the design of novel direct thrombin inhibitors are discussed, which may very well contribute to future developments of potent anticoagulants.

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“…Synthetically, inhibitor 1 and its analogues were assembled similarly to the method reported by Costanzo et al 25 by peptide coupling of warhead-functionalized P1 fragment 8 with protected P4−P2 fragment 10 (Schemes 1 and 2). The synthesis of inhibitor 1 is shown as an example.…”

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confidence: 99%

Design and Synthesis of Potent, Selective Inhibitors of Matriptase

Colombo

Désilets

Duchêne

et al. 2012

ACS Med. Chem. Lett.

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Matriptase is a member of the type II transmembrane serine protease family. Several studies have reported deregulated matriptase expression in several types of epithelial cancers, suggesting that matriptase constitutes a potential target for cancer therapy. We report herein a new series of slow, tightbinding inhibitors of matriptase, which mimic the P1−P4 substrate recognition sequence of the enzyme. Preliminary structure−activity relationships indicate that this benzothiazole-containing RQAR-peptidomimetic is a very potent inhibitor and possesses a good selectivity for matriptase versus other serine proteases. A molecular model was generated to elucidate the key contacts between inhibitor 1 and matriptase.

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In-Depth Study of Tripeptide-Based α-Ketoheterocycles as Inhibitors of Thrombin. Effective Utilization of the S₁‘ Subsite and Its Implications to Structure-Based Drug Design.

Cited by 15 publications

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EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

Direct thrombin inhibitors – a survey of recent developments

Design and Synthesis of Potent, Selective Inhibitors of Matriptase

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In-Depth Study of Tripeptide-Based α-Ketoheterocycles as Inhibitors of Thrombin. Effective Utilization of the S1‘ Subsite and Its Implications to Structure-Based Drug Design.

Cited by 15 publications

References 0 publications

EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

EMBM − A New Enzyme Mechanism-Based Method for Rational Design of Chemical Sites of Covalent Inhibitors

Direct thrombin inhibitors – a survey of recent developments

Design and Synthesis of Potent, Selective Inhibitors of Matriptase

Contact Info

Product

Resources

About

In-Depth Study of Tripeptide-Based α-Ketoheterocycles as Inhibitors of Thrombin. Effective Utilization of the S₁‘ Subsite and Its Implications to Structure-Based Drug Design.